The [unreadable]-amyloid precursor protein ([unreadable]APP) is connected to Alzheimer's disease by genetics, pathology, and biochemistry. A secreted form of this protein, sAPPa, can inhibit the activity of a class of neurotransmitter receptor called the NMDA receptor. This "neuromodulation" requires the unique C-terminus of sAPPa;the secreted form of [unreadable]APP produced by [unreadable]-secretase (sAPP[unreadable]) differs at the C-terminus and is much diminished in neuromodulatory activity. These differences in bioactivity suggest differences in binding to cell-surface receptor(s). Preliminary results suggests that the bioactivity of sAPPa is mediated by binding to the ApoE receptor 2 (apoE-R2;a.k.a. LRP8), known to be a receptor for another neuromodulatory protein, Reelin. Reelin facilitates NMDA-R activity critical for memory by eliciting homodimerization of LRP8 or a closely related receptor termed VLDL-R. Existing as a monomer at low concentrations, sAPPa could be envisioned to bind one or both of these receptors without effecting their dimerization. It is hypothesized here that the neuromodulatory activity of sAPPa is mediated by monovalently binding a LRP8 and/or VLDL-R molecule, inhibiting the receptor(s)'s dimerization and signaling. This effect may be lost as sAPPa homodimerizes at higher concentrations. Key components of this hypothesis will be tested by accomplishment of two main objectives. First, the binding of sAPPa to LRP8 and VLDL-R will be tested by forced expression of these receptors in an ectopic cell type. Second, the role of LRP8 and VLDL-R in the neuromodulatory activity of sAPPa will be examined by reducing their expression in mammalian neurons. In addition to providing key mechanistic insights into the basic biology of sAPPa, this project will facilitate future studies exploring a broader hypothesis that focuses on the dimerization potential of other LRP ligands such as apolipoprotein E. PUBLIC HEALTH RELEVANCE: Most immediately, the results of this study will influence hypotheses about the function of the [unreadable]-amyloid precursor protein ([unreadable]APP), which may play a role in Alzheimer's disease as well as aspects of normal brain development that are compromised in human conditions such as cerebral palsy and Down's syndrome. The findings from this project will also be expanded into a larger hypothesis concerning the interactions of [unreadable]APP with apolipoprotein E (ApoE), with greater emphasis on Alzheimer's disease, where genetic variations in both [unreadable]APP and ApoE contribute to disease etiology.